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ORIGINAL RESEARCH |
From the Ehrling Bergquist Hospital, Offutt Air Force Base, Bellevue, Nebraska and Wilford Hall Medical Center, Lackland Air Force Base, Lackland, Texas.
Address reprint requests to: Michael C. Gordon, MD Lackland Air Force Base Wilford Hall Medical Center Department of Obstetrics and Gynecology 859th MDOS/MMNO 2200 Bergquist Drive, Suite 1 Lackland Air Force Base, TX 78236-5300 E-mail: mike.gordon{at}59mdw.whmc.af.mil
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Abstract |
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Methods: Ten women at risk of preterm delivery had three weekly low-dose (1 µg) ACTH stimulation tests with the first one between 24 and 25 weeks’ gestation. Immediately after the first and second ACTH stimulation tests, we gave each woman a 12-mg betamethasone dose intramuscularly and repeated it 24 hours later. The third ACTH stimulation test was 1 week after the second course of betamethasone. Serum cortisol levels were measured before (baseline) and 30 minutes after ACTH administration.
Results: All subjects had normal baseline and stimulated cortisol levels for the first ACTH stimulation test. Mean baseline serum cortisol levels decreased with each ACTH stimulation test, from 25.4 ± 4.8 µg/dL (before betamethasone) to 4.3 ± 4.0 µg/dL (1 week after the second course of betamethasone) (P < .001). The mean stimulated cortisol levels also decreased from 33.0 ± 4.3 µg/dL (before betamethasone) to 11.8 ± 6.4 µg/dL (1 week after the second course of betamethasone) (P < .001). Compared with initial ACTH stimulation tests, laboratory evidence of adrenal suppression occurred in four patients 1 week after the first course of betamethasone and in seven patients after the second course. No signs or symptoms of Addisonian crisis occurred antepartum or intrapartum.
Conclusion: Antenatal administration of betamethasone produced measurable adrenal suppression in women at risk of preterm delivery. The number of women with adrenal suppression increased each week that antenatal betamethasone was repeated.
Antenatal administration of glucocorticoids to women at risk of preterm delivery decreases the likelihood of neonatal respiratory distress syndrome (RDS), necrotizing enterocolitis, intraventricular hemorrhage, and perinatal death.1,2 Betamethasone, the drug most commonly used for this purpose, is a long-acting glucocorticoid with a potency approximately 30 times that of hydrocortisone. Because maximal benefits of the drug occur 2–7 days after intramuscular (IM) administration, some clinicians advocate weekly courses of betamethasone for women who remain at risk of preterm delivery. It is possible that repetitive doses of betamethasone might cause maternal adrenal suppression. We studied women at risk of preterm delivery by using a low-dose ACTH stimulation test to detect adrenal suppression after weekly administration of betamethasone.
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Materials and Methods |
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Each subject had low-dose ACTH testing at entry and weekly for the next 2 weeks, for a total of three tests. Low-dose ACTH testing consisted of measuring nonfasting venous cortisol levels (baseline cortisol) at 8:00 to 10:00 AM, administering cosyntropin (Cortrosyn; Organon Inc., West Orange, NJ) 1 µg intravenously (IV) as a bolus, and measuring serum cortisol levels 30 minutes later (stimulated cortisol). Cosyntropin was prepared by diluting 250 µg of the stock product in 500 mL of normal saline and stored at 4C for up to 4 months. Cosyntropin prepared that way was shown to be stable for that length of time.3 Blood was stored at room temperature until a clot formed, then centrifuged to obtain serum for assay. Cortisol was measured by competitive enzyme immunoassay using the AIA-PACK CORT on the TOSOH AIA immunoassay analyzer (TOSOH Medics Inc., South San Francisco, CA).
Immediately after the first and second ACTH stimulation tests, we gave each patient a 12-mg IM betamethasone dose and repeated it 24 hours later. The third ACTH stimulation test occurred 1 week after the second course of betamethasone.
Baseline and stimulated cortisol levels were compared by repeated measures analysis of variance with Bonferroni post hoc testing for significance. We had difficulty ensuring that the data were normally distributed because of the small sample (n = 10), so we also chose to evaluate the data using nonparametric repeated measures analysis of variance with nonparametric post hoc tests. We used Friedman test for repeated measures with Wilcoxon signed-rank test for post hoc testing. The statistical results did not differ between parametric and nonparametric analysis, so we have chosen to report our results using the parametric tests. McNemar test was used to determine whether the number of baseline and stimulated cortisol levels classified as normal for each ACTH stimulation test changed throughout the study. Baseline cortisol levels greater than 5 µg/dL and stimulated cortisol levels greater than 18 µg/dL were considered normal for the purpose of this study. A baseline cortisol level of greater than 5 µg/dL historically has been used as the normal morning level. A stimulated cortisol level greater than 18 µg/dL is the accepted definition for normal for nonpregnant adults.4,5 Prior studies showed that some individuals on glucocorticoid replacement with morning cortisol levels greater than 5 µg/dL still had adrenal insufficiency, with stimulated cortisol levels less than 18 µg/dL, and were considered to have adrenal suppression.4 Whether pregnancy affects normal values of low-dose ACTH stimulation test is not known. P < .05 was considered statistically significant.
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Results |
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Mean baseline and stimulated serum cortisol levels (± standard deviation) are presented in Table 1
. Mean baseline cortisol levels for each ACTH stimulation test differed statistically significantly (P < .001). Post hoc testing showed a significant difference between mean baseline cortisol levels. Mean stimulated cortisol levels for each ACTH stimulation test also differed statistically significantly (P = .001). Post hoc testing showed a difference between all mean stimulated cortisol levels.
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Discussion |
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For this study we chose the low-dose (1 µg) ACTH stimulation test to evaluate the hypothalamic-pituitary-adrenal axis because the traditional higher dose test (250 µg) could evoke a normal response even in women with known adrenal insufficiency.8 The low-dose test has been more sensitive in detecting mild adrenal insufficiencies in other studies.9–12
McKenna and colleagues used a low-dose ACTH stimulation test (0.5 µg) to examine the hypothalamic-pituitary-adrenal axis in 18 women who had received at least two courses of antenatal steroids and compared the results with those of six women who had not received steroids (McKenna DS, Wittber GM, Samuels P. The effects of repeated doses of antenatal corticosteroids on maternal adrenal function [abstract]. Am J Obstet Gynecol 1999;180:S15). They found lower baseline and stimulated cortisol levels among the group that received steroids. However, women in the study group were presumably in preterm labor and were not tested before administration of betamethasone, so we cannot rule out the possibility of selection bias. Corticotropin-releasing hormone has been shown to be elevated in women in preterm labor, possibly affecting serum cortisol levels and ACTH testing.13,14 A major difference between that study and ours was that our patients served as their own controls and were not in preterm labor. Other than the report by McKenna et al, use of the low-dose ACTH stimulation test has not been reported in pregnant women.
Our study is important because it showed the development of adrenal insufficiency in previously normal pregnant women after just two standard courses of betamethasone and that adrenal insufficiency was detectable 1 week after the second course. The natural history of betamethasone-induced adrenal suppression in pregnant women is not known. We did not test women 2 weeks after only a single course. However, by doing the ACTH stimulation tests weekly, we found a more profound effect on the maternal hypothalamic-pituitary-adrenal axis after the second course which suggests that repetitive weekly courses of glucocorticoids might affect the maternal hypothalamic-pituitary-adrenal axis more significantly than administering only a single dose.
We recognize that the size of this study and the lack of adverse clinical outcomes preclude drawing meaningful conclusions about the clinical implications of our findings. We urge caution in administering multiple courses of betamethasone until larger studies can clarify the risks and benefits of repeated weekly doses. Because we found measurable adrenal suppression in most women after only two courses of betamethasone, we also encourage physicians to be more aware of clinical signs of adrenal insufficiency when caring for women who have received repetitive courses of that drug.
Other concerns about multiple courses of glucocorticoids include the possibility of fetal adrenal suppression and growth restriction. A review of fetal complications after maternal steroid administration found a single case of an infant with Cushing syndrome that developed after seven courses of maternal betamethasone.15 That syndrome has not been a clinically reported phenomenon in infants of women who received fewer courses of treatment, but the number of antenatal steroid courses that can be administered safely while avoiding that complication is not known. Growth restriction has been reported in sheep after preterm maternal administration of single and multiple courses of glucocorticoids, and it increased with the number of courses given.16–18 Growth restriction after steroid treatment to induce lung maturity has not been reported in human studies. Until further studies show a definite benefit of weekly doses of antenatal corticosteroids, it might be prudent to treat women when they present, but to withhold additional steroid therapy unless concern of preterm delivery recurs.
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Footnotes |
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The views expressed in this article are those of the authors and should not be construed as the official policy or position of the United States Air Force, the Department of Defense, or the United States Government.
Received December 30, 1999. Received in revised form February 24, 2000. Accepted March 16, 2000.
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References |
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2. NIH Consensus Conference. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995;273:413–8.[Abstract]
3. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, et al. Adrenocotropin stimulation tests: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773–8.[Abstract]
4. Grinspoon SK, Biller BMK. Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923–31.[Medline]
5. Oelkers W. Adrenal insufficiency. N Engl J Med 1996;335:1206–12.
6. Dorr HG, Versmold HT, Sippell WG, Bidlingmaier F, Knorr D. Antenatal betamethasone therapy: Effects on maternal, fetal, and neonatal mineralocorticoids, glucocorticoids, and progestins. J Pediatr 1986;108:990–3.[Medline]
7. Charnvises S, de Fencl M, Osathanondh R, Zhu MG, Underwood R, Tulchinsky D. Adrenal steroids in maternal and cord blood after dexamethasone administration at midterm. J Clin Endocrinol Metab 1985;61:1220–2.[Abstract]
8. Streeten DHP, Anderson GH, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1994; 81:285–90.
9. Broide J, Kivity S, Golander A, Dickstein G, Spirer Z, Weisman Y. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995;80:1243–6.[Abstract]
10. Tordjman K, Jaffe A, Grazas N, Apter C, Stern N. The role of the low dose (1 µg) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1994;80: 1301–5.
11. Rasmuson S, Olson T, Hagg E. A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 1996;44:151–6.[Medline]
12. Thaler LM, Blevins LS. The low dose (1 µg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998;83:2726–9.
13. Korebritis C, Yu DHT, Ramirez MMR, Marinoni E, Bocking AD, Challis JRG. Antenatal glucocorticoid administration increases corticotropin-releasing hormone in maternal plasma. Br J Obstet Gynaecol 1998;105:556–61.[Medline]
14. Warren WB, Patrick SL, Goland RS. Elevated maternal plasma corticotropin-releasing hormone levels in pregnancies complicated by preterm labor. Am J Obstet Gynecol 1992;166:1198–207.[Medline]
15. Bradley BS, Kumar SP, Mehta PN, Ezhuthachan SG. Neonatal cushingoid syndrome resulting from serial courses of antenatal betamethasone. Obstet Gynecol 1994;83:869–72.[Abstract]
16. Johnson JWC, Mitzner W, Beck JC, London WT, Sly DL, Lee PA, et al. Long-term effects of betamethasone on fetal development. Am J Obstet Gynecol 1981;141:1053–63.[Medline]
17. Jobe AH, Wada N, Berry LM, Ikegami M, Ervin G. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep. Am J Obstet Gynecol 1998;178:880–5.[Medline]
18. Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med 1997;156:178–84.
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